1. Field of the Invention
The present invention relates to a manufacturing method of new bioresorbable calcium phosphate ceramics, and more particularly to a method of manufacturing dicalcium phosphate ceramics and dicalcium phosphate/hydroxyapatite (HA) biphasic ceramics useful as bone graft materials, bone substitutes and bone fillers.
2. Description of Related Art
The major inorganic constitute of hard tissue is biological apatite. For example, bone has 65% to near 70% of biological apatite, and teeth contain more than 98% biological apatite. Hydroxyapatite (HA) is a calcium phosphate compound which has similar crystal structure as biological apatite. In principle, HA should be an ideal candidate as hard tissue replacement material. However, the precipitated HA particles are very fine powder. Because of manipulation requirement, this hinders the use of precipitated HA as useful hard tissue replacement material. Similar problems exist for other precipitated calcium phosphate particles, such as dicalcium phosphate for medical use.
In the early 1980, attempts were made to prepare calcium phosphate ceramics in the granular form or block form by ceramic sintering technique. In the last thirty year or so, many types of calcium phosphate ceramics have been prepared. Among these HA, α- and β-tricalcium phosphate (TCP) ceramics have been extensively studies. Clinical studies confirmed that most of the calcium phosphate ceramics with Ca/P mole ratio equal to one or higher, such as dicalcium phosphate, HA, TCP and tetracalcium phosphate (TTCP), have excellent compatibility and are well accepted by the hard tissue and soft tissue. Experiment results indicated that dense HA is non-resorbable while other porous calcium phosphate ceramics are resorbable. In general, β-TCP ceramic resorbs faster than HA but has weaker mechanical strength than HA. To obtain ceramics combining good mechanical properties with bioresorption, a biphasic calcium phosphate (BCP) ceramic has been prepared. These biphasic ceramics are a mixture of HA and β-TCP. Most of the above ceramics is either resorbed too slowly or difficult to control the bioresorption rate.
Brown and Chow in 1986 were the first to present calcium phosphate in the cement form for medical applications. The main constitute of the cement is TTCP and dicalcium phosphate, and the main reaction product is HA. After that, calcium phosphate cements with different formulations have been developed. Main advantages of calcium phosphate cement are moldable. Calcium phosphate cements developed can be classified according to their reaction products. Basically, there are two major types of calcium phosphate cements namely the HA cement and dicalcium phosphate dihydrate (DCPD) cement. Similar to high temperature HA, HA cement is resorbed very slowly. Major constitutes of DCPD are basic calcium phosphate, such as α- or β-TCP or HA, with acidic phosphate compounds, such as phosphoric acid or monocalcium phosphate, together with some setting solution. In general, this type of cement is quite acidic. Beside the reaction product is DCPD, it also contains considerable amount of unreacted constitute. The physical and chemical properties of this type of cement also vary considerable. For example, using β-TCP to prepare DCPD cement, it is always keep basic calcium phosphate in much excess. Beside, it always keeps some crystal growth inhibitor to control the setting time. After setting, beside the formed DCPD, it also contains the excess unreacted product and some setting regulating reagent. On the other hand, if stoichiometric amount are used, the setting cement is too acidic for use. If HA is used instead of TCP, the setting time is difficult to control and the setting cement is too acidic. Similar to precipitated HA, dicalcium phosphate prepared from precipitated method is also a fine powder and have manipulation problem. Even the powder can be very pure; it can not be used for bone filler or bone substitute because of manipulation problem.
In recent year, calcium sulfate also has been used as bone filler or replacement material. However, the major drawbacks are the rapid bioresorption and low strength. This makes it less useful in larger defects and when fracture healing exceeds 4-6 weeks. From practical point of view, bioceramics for bone filler or as bone substitute materials should have both controllable physical and chemical properties, such as mechanical strength and bioresorption rate.
There are many types of calcium phosphate compounds. Among these are dicalcium phosphate, calcium pyrophosphate, α-TCP, β-TCP, HA and TTCP. Some of these compounds can be prepared only by high temperature technique, such as TTCP and α-TCP. Some of them can only form from precipitation method. Among these are DCPD and DCPA. Other calcium phosphate minerals, such as HA, apatite minerals, and calcium pyrophosphate, can be prepared by either high temperature sintering technique or the precipitation method. For medical applications, such as bone substitute or bone filler, most of the calcium phosphate ceramics are prepared as granular form or block form by high temperature sintering technique. For example, commercial calcium phosphate ceramics for medical applications are block form or granular form of HA, β-TCP and biphasic calcium phosphate which contains both HA and β-TCP. Precipitated calcium phosphate compounds are always very fine powder. Because of manipulation difficulties, precipitated calcium phosphate materials have limited applications as bone substitute or bone filler. Pure DCPD are normally prepared by precipitation method. DCPA can be obtained by precipitation method or by dehydrating DCPD at high temperature. Dicalcium phosphates prepared by this method are also very fine powder. They have difficulties to be used in the area of bone graft or bone filler. Granular form of dicalcium phosphate can be prepared from granulation technique. However, it always contains binder in the preparation process. Besides, granule preparation from granulation technique is not strong. These cause the precipitated dicalcium phosphate having difficulties for using in the hard tissue area.
Moreover, it is well known that DCPD can be precipitated from calcium phosphate saturated solution at pH value near 4 or lower. However, when the pH of calcium phosphate saturated solution is near 7 or higher, the precipitated calcium phosphate is HA or apatite minerals.
Therefore, most of the above cements or ceramics have certain disadvantages. The present invention is aimed to prepare pure dicalcium phosphate (either dihydrate or anhydrous) and its composite mixture with HA for medical applications especially in the bone substitute or bone filler area to overcome the above disadvantages.